Drug delivery particle formulations with targeting moieties

ABSTRACT

A targeted drug delivery complex containing a particle, a targeting moiety electrostatically attached to the particle, and an active pharmaceutical ingredient attached to or dispersed or dissolved within the particle is provided. Also provided are pharmaceutical formulations containing a plurality of the complexes as well as methods for use in targeting an active pharmaceutical ingredient to a selected cell or tissue and production of such formulations.

This patent application claims the benefit of priority from U.S.application Ser. No. 61/720,112, filed Oct. 30, 2012, teachings of whichare incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a targeted drug delivery complexcomprised of a particle, a targeting moiety attached to the particle anda pharmaceutically active ingredient attached to or dispersed ordissolved with the particle. The present invention further relates toparticle formulations containing a plurality of these targeted drugdelivery complexes. The present invention also relates to methods oftargeting an active pharmaceutical ingredient to a cell or tissue viaformulation of the active pharmaceutical ingredient as a targeted drugdelivery complex. In one embodiment, the active pharmaceuticalingredient is a toxin.

SUMMARY OF THE INVENTION

An aspect of the present invention relates to a targeted drug deliverycomplex comprised of a particle, a targeting moiety attached to theparticle and an active pharmaceutical ingredient attached to ordispersed or dissolved with the particle. In one embodiment, the activepharmaceutical ingredient is a toxin.

Another aspect of the present invention relates to a pharmaceuticalformulation comprising a plurality of the targeted drug deliverycomplexes and a pharmaceutically acceptable vehicle.

Another aspect of the present invention relates to a method fortargeting an active pharmaceutical ingredient to a selected cell ortissue comprising formulating the active pharmaceutical ingredient as atargeted drug delivery complex.

Another aspect of the present invention relates to a method forproducing a pharmaceutical formulation targeted to a selected cell ortissue. The method comprises attaching a targeting moiety for theselected cell or tissue to a plurality of particles and furtherdispersing or dissolving with or attaching an active pharmaceuticalingredient to the plurality of particles.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram of one embodiment of a targeted drug deliverycomplex of the present invention. In this embodiment, the targetingmoiety attached to the particle is an antibody. This embodiment furthercontains an active pharmaceutical ingredient, in particular a toxin,dispersed within the particle.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides targeted drug delivery complexes,pharmaceutical formulations containing of a plurality of these targeteddrug delivery complexes in a pharmaceutically acceptable vehicle,methods for their use in targeting an active pharmaceutical ingredientto a selected cell or tissue and methods for production of thesetargeted drug delivery complexes.

Targeted drug delivery complexes of the present invention comprise aparticle, an active pharmaceutical ingredient (API), and a targetingmoiety.

Particles of the targeted drug delivery complexes of the presentinvention can be made from any number of materials or matrixesincluding, but in no way limited to, waxes, natural polymers, andsynthetic polymers. The particles may be biodegradable such as particlesconstructed wholly or partially from poly (lactic-co-glycolic acid)(PLGA).

In one embodiment, lipids are used as the matrix for the particle of thetargeted drug delivery complex. Examples of lipids which can be usedinclude, but are not limited to, carnauba wax, bees wax, behenyl alcohol(docosanol), cetyl alcohol, microcrystalline triglycerides such asdynasan 118 (glyceryl tristearate) and polyethylene wax. In oneembodiment, the lipid is carnauba wax including a carnauba comprisingaliphatic esters, diesters of 4-hydroxycinnamic acid,ω-hydroxycarboxylic acids and fatty acid alcohols.

However, as will be understood by the skilled artisan upon reading thisdisclosure, particle matrices may be comprised of non-lipids as well.

In one embodiment, the matrix of the particle further comprises asurfactant. Surfactants that may be used in the particle matricesinclude cationic, anionic and non-ionic surfactants. Examples of suchsurfactants include, but are not limited to, cetyl triammonium bromide(CTAB), N-[1-(2,3-Dioleoyloxy)]-N,N,N-trimethylammonium propanemethylsulfate DOTAP, cetylpyridinium bromide (CPB), polysorbatesurfactants such as Tween 20, Tween 80 (polyoxyethylene sorbitanmonoloaurate), polyethylene stearyl ether such as Brij 70, sodiumstearate, sodium myristate, sodium dodecyl sulfate, Dioctyl sodiumsulfosuccinate such as AOT and combinations thereof. The surfactant maypresent in a level from about 0.01% to about 10%, or from about 0.05% toabout 5% or from about 0.1% to about 2% or from about 0.5% to about 2%or from about 1.0% to about 2.0%.

In one embodiment, the surface charge on the matrix is altered tooptimize attachment of the targeting moiety by attaching chargedmoieties or adjusting the type of surfactant and/or matrix used in theproduction of the targeted drug delivery complex.

Particle size is preferably less than 1 μm with the particles ranging insize between about 10 nm to 1000 nm or between about 20 nm to about 900nm or from about 30 nm to abut 800 nm or from about 40 nm to about 700nm or from about 50 nm to about 650 nm or from about 100 nm to about 750nm or from about 200 nm to about 750 nm or from about 300 nm to about750 nm or from about 300 nm to about 650 nm or from about 400 nm toabout 750 nm or from about 400 nm to about 660 nm or from about 500 nmto about 750 nm or from about 500 nm to about 650 nm. Particle shape maybe, but is not limited to spheres, prolate and oblate spheroids,cylindrical, and irregular shapes.

The particles may be neutral or may be positively or negatively chargedand may have a combination of surface charges resulting in a netneutral, positive or negative charge.

The targeted drug delivery complexes of the present invention furthercomprise an API. The API may be incorporated into the drug deliveryparticles of the present invention by one or several of the followingways. In one embodiment, the API can be solubilized in the particleresulting in a solid or liquid solution of the API in the particlematerial or matrix. In an alternative embodiment, the API can bedispersed within the particle material or matrix such that discretemulti-atom units of the API exist. In yet another embodiment, the APIcan be attached to the outside of the particle in molecular orparticulate form.

Examples of APIs useful in the present invention include, but are notlimited to, analgesics, anti-anginal agents, anti-asthmatics,anti-arrhythmic agents, anti-angiogenic agents, antibacterial agents,anti-benign prostate hypertrophy agents, anti-cystic fibrosis agents,anti-coagulants, anti-depressants, anti-diabetic agents, anti-epilepticagents, anti-fungal agents, anti-gout agents, anti-hypertensive agents,anti-inflammatory agents, anti-malarial agents, anti-migraine agents,anti-muscarinic agents, anti-neoplastic agents, anti-obesity agents,anti-osteoporosis agents, anti-parkinsonian agents, anti-protozoalagents, anti-thyroid agents, anti-urinary incontinence agents,anti-viral agents, anxiolytics, beta-blockers, cardiac inotropic agents,cognition enhancers, corticosteroids, COX-2 inhibitors, diuretics,erectile dysfunction improvement agents, essential fatty acids,gastrointestinal agents, histamine receptor antagonists, hormones,immunosuppressants, keratolyptics, leukotriene antagonists, lipidregulating agents, macrolides, muscle relaxants, non-essential fattyacids, nutritional agents, nutritional oils, protease inhibitors andstimulants.

In one embodiment, the active pharmaceutical ingredient is a toxin.

The targeted drug delivery complexes of the present invention furthercomprise a targeting moiety attached to the outside of the particle. Thetargeting moiety is attached to the particle electrostatically such thatthe attachment does not require any covalent alteration of the targetingmoiety. In one embodiment, the targeting moiety binds to a selected cellor tissue. Examples of targeting moieties include, but are not limitedto, antibodies, Fabs, aptamers, oligonucleotides, small molecules andcarbohydrates.

The entire complex comprising the particle, API and targeting moiety isreferred to herein as a targeted drug delivery complex. The targeteddrug delivery complex the present invention have an average diameter ofless than 100 μm, more preferably less than 10 μm, more preferably lessthan 1 μm.

Pharmaceutical formulations in accordance with the present inventioncomprise a plurality of the targeted drug delivery complexes and apharmaceutically acceptable vehicle.

Pharmaceutically acceptable vehicles for use with the targeted drugdelivery complexes of the present invention are well known in the artand taught in standard reference texts such as Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985.

The targeted drug delivery complexes of the present invention are usefulin methods of targeting an active pharmaceutical ingredient to aselected cell or tissue and producing pharmaceutical formulationstargeted to a selected cell or tissue. In these methods, a targetingmoiety for the selected cell or tissue is electrostatically attached toa particle. The particle further comprises the active pharmaceuticalingredient to be targeted to the cell to tissue dispersed or dissolvedwith or attached to the particle.

1. A targeted drug delivery complex comprising a particle, a targetingmoiety attached electrostatically to the particle, and an activepharmaceutical ingredient dispersed or dissolved with or attached to theparticle.
 2. The targeted drug delivery complex of claim 1 wherein theparticle is made of a matrix comprising a wax, a natural polymer and/ora synthetic polymer.
 3. The targeted drug delivery complex of claim 1wherein the targeting moiety binds to a selected cell or tissue.
 4. Thetargeted drug delivery complex of claim 1 wherein the targeting moietycomprises an antibody, a Fab, an aptamer, an oligonucleotide, a smallmolecule or a carbohydrate.
 5. The targeted drug delivery complex ofclaim 1 wherein the active pharmaceutical ingredient is selected fromthe group comprising analgesics, anti-anginal agents, anti-asthmatics,anti-arrhythmic agents, anti-angiogenic agents, antibacterial agents,anti-benign prostate hypertrophy agents, anti-cystic fibrosis agents,anti-coagulants, anti-depressants, anti-diabetic agents, anti-epilepticagents, anti-fungal agents, anti-gout agents, anti-hypertensive agents,anti-inflammatory agents, anti-malarial agents, anti-migraine agents,anti-muscarinic agents, anti-neoplastic agents, anti-obesity agents,anti-osteoporosis agents, anti-parkinsonian agents, anti-protozoalagents, anti-thyroid agents, anti-urinary incontinence agents,anti-viral agents, anxiolytics, beta-blockers, cardiac inotropic agents,cognition enhancers, corticosteroids, COX-2 inhibitors, diuretics,erectile dysfunction improvement agents, essential fatty acids,gastrointestinal agents, histamine receptor antagonists, hormones,immunosuppressants, keratolyptics, leukotriene antagonists, lipidregulating agents, macrolides, muscle relaxants, non-essential fattyacids, nutritional agents, nutritional oils, protease inhibitors andstimulants.
 6. The targeted drug delivery complex of claim 2 wherein theactive pharmaceutical ingredient is dissolved, in a liquid or solidsolution, in the particle matrix and/or dispersed within the particlematrix and/or adhered to a particle surface.
 7. The targeted drugdelivery complex of claim 1 wherein the active pharmaceutical ingredientis not covalently modified.
 8. The targeted drug delivery complex ofclaim 1 wherein the targeting moiety is not covalently modified.
 9. Apharmaceutical formulation comprising a plurality of targeted drugdelivery complexes of claim 1 and a pharmaceutically acceptable vehicle.10. A method for targeting an active pharmaceutical ingredient to aselected cell or tissue comprising formulating the active pharmaceuticalingredient as a targeted drug delivery complex of claim
 1. 11. A methodfor producing a pharmaceutical formulation targeted to a selected cellor tissue, said method comprising: dispersing or dissolving with orattaching an active pharmaceutical ingredient in or on a particle; andelectrostatically attaching a targeting moiety for the selected cell ortissue to said particle.